Metals are an important, emerging class of carcinogens although their mechanism of action remains largely unknown. Arsenic (As) is known to consume cellular methyl groups but its mode of carcinogenic action is undefined. We recently found in epithelial cells transformed by chronic low level exposure to As that genomic DNA is hypomethylated. Thus, As transformation is associated with DNA hypomethylation, a state often linked with gene activation and likely connected to acquisition of malignant phenotype. Acutely, As activates the proto-oncogenes c-myc and c-jun, both important genes in control of proliferation. Our further studies have shown several gene activations occur during As-induced malignant transformation, including possible activation of the c-myc gene. For cadmium (Cd) we have found a clear genetic basis in carcinogenic sensitivity exists. The metal-binding protein, metallothionein (MT), may play a fundamental role in sensitivity to Cd carcinogenicity. The basal and induced activity of the MT gene is clearly associated with tolerance to Cd genotoxicity. Cellular preactivation of the MT gene markedly reduced Cd genotoxicity, while cells with a quiescent MT gene are highly sensitive to Cd genotoxicity. Cd-induced proto-oncogene activation is likewise blocked by prior MT activation. MT is poorly expressed and unresponsive to stimulation in the specific lobe of the rat prostate that is sensitive to Cd tumorigenesis. The testicular MT gene is poorly activated by Cd and does not play a role in the induced tolerance to Cd. Lead (Pb) is considered the single most hazardous substance to the U.S. population, though its carcinogenic potential is controversial. Previously, Pb carcinogenicity was considered to result from non-genotoxic mechanisms entailing chronic proliferative repair. We assessed the carcinogenicity of short-term gestational/lactational Pb exposure in mice. Pb was clearly a renal carcinogen in treated offspring. As Pb-induced renal tumors occurred long after short-term exposure and in the absence of chronic nephropathy, contrary to the prevailing beliefs, Pb may be a genotoxic carcinogen. This is an extremely important finding in evaluating human risk. Molecular and cellular models are now being developed in order to help define the genotoxic potential of this very important environmental contaminant. A key success in this effort has been the development of a Pb-transformed renal epithelial cell line in which genetic events can be studied.